Treating the flu?

They walked out together into the fine fall day, scuffling bright ragged leaves under their feet, turning their faces up to a generous sky really blue and spotless. At the first corner they waited for a funeral to pass, the mourners seated straight and firm as if proud in their sorrow. [...] “It seems to be a plague,” said Miranda, “something out of the Middle Ages. Did you ever see so many funerals, ever?”
— from “Pale Horse, Pale Rider” by Katherine Anne Porter (1939)

And I looked, and behold a pale horse: and his name that sat on him was Death, and Hell followed with him.
— Revelations 6.8 (King James Version)

In 1918-1919 between 50 and 100 million people worldwide died from the flu. The "Spanish Flu" spread to nearly every part of the world with amazing speed, helped perhaps by the thousands of soldiers returning from Europe after the end of World War I. There was little that could be done to help the sick, and often people who were healthy one day were dead the next. The Spanish Flu was remarkable at the time in that it primarily killed young healthy adults, whereas most often it is very young children and elderly people who die from infectious disease.

Oddly enough, after going through two successive waves of infection and mortality, the Spanish Flu pandemic disappeared almost abruptly. By the end of the 20th century, it was almost forgotten, and influenza had come to be regarded as one of the many childhood diseases that most people went through without much difficulty.

The situation today is quite different. Everyone is now highly sensitized to the threat of influenza. Stories about the so-called "Bird Flu" and now the "Swine Flu" have appeared regularly on television and in newspapers. Our society is more mobile than ever before, and we have seen examples of the rapid spread of diseases worldwide in recent years. Population is far more dense than it was in 1918, and diseases spread and mutate in crowded cities around the world far faster than ever before. People are deeply concerned about the possibility of a new influenza pandemic that could rival the Spanish Flu.

On the other hand, we also now know much more about how to prevent and how to treat illnesses like influenza. The best way to slow or stop the spread of influenza is through public health measures - simple things like frequent hand washing and avoiding contact with infected people. In addition, immunization is an important protective measure if a safe and effective vaccine can be developed.

But what about treating people who are already infected? Because influenza is a viral disease, antibiotics that can deal with bacterial infections will not work. The story of how drugs to treat serious cases of influenza were developed shows how structural biology, biochemistry and synthetic organic chemistry work hand-in-hand to produce new and useful chemical substances. It remains to be seen if they can help in the event of a pandemic outbreak, which many people think is a question of "when" rather than "if".

Treating the flu? Part 1: The Influenza Virus

Influenza is caused by RNA viruses of the family Orthomyxoviridae. These virions are roughly 80-120 microns in diameter. Their surfaces consist of a lipid bilayer derived from the membrane of the host cell, which is decorated by glycoproteins that project like spikes from the viral particle. About 80% of these spikes are hemagglutinin, a protein that facilitates binding the virion to a host cell. The remainder areneuraminidase, which is an enzyme that cleaves glycosidic linkages to the sugar neuraminic acid (also calledsialic acid). You have probably heard the different strains of the flu virus ("serotypes") referred to as "H1N1" or "H5N1". These names refer to the different subtypes of the two surface glycoproteins, differences that distinguish the serotypes immunogenically.

There are several outstanding web sites that will tell you much more about the influenza virus. There is no point in just repeating what they contain here, so if you want more information you can follow the links below. Otherwise, click here to move to the next part of the drug development story.

• Some really nice electron micrographs of real influenza virions that show the hemagglutinin and neuraminidase "spikes".
• Influenza 101 - the virology blog. This takes you through the structure of the virus, how it enters cells, reproduces and then leaves to infect other cells. Very good quality information and very easy reading.
• Influenza Virus from Kimball's Biology Pages
• Influenza viruses on Wikipedia.

Treating the flu? Part 2: Targets for therapy

A drug must act by binding to and modulating the activity of some target receptor or enzyme. Viruses do not present very many potential targets because they typically have only a few unique proteins coded in their genomes. Recall that viruses hi-jack the enzymes of the host cell to manufacture new virions.

The Influenza A genome consists of 8 strands of RNA:

1. The HA gene. It encodes the hemagglutinin.
2. The NA gene. It encodes the neuraminidase.
3. The NP gene encodes the nucleoprotein. Influenza A, B, and C viruses have different nucleoproteins.
4. The M gene encodes two proteins (using different reading frames of the RNA): a matrix protein M1 and an ion channel M2 spanning the lipid bilayer.
5. The NS gene encodes two different non-structural proteins that are found in the cytoplasm of the infected cell but not within the virion itself.
6. – 8. one RNA molecule (PA, PB1, PB2) for each of the 3 subunits of the RNA polymerase.

Drugs against Influenza A could potentially be developed to inhibit the activity of any of the products of the influenza genome, but in fact only drugs acting against the NA (neuraminidase) and the M2 (ion channel) proteins have been successfully developed to date.

The M2 inhibitors amantadine and rimantadine were the first effective drugs against influenza, but the M2 protein seems quite easy for the virus to modify so resistance rapidly develops against these drugs. The latest H1N1 virus that is causing pandemic concern is resistant to both amantadine and rimantadine. The drugs that are being used against current pandemic threat strains target the viral neuraminidase, and it is these that form the basis of our discussion on drug development.

Treating the flu? Part 3: Neuraminidase

This is only a very short description of this important enzyme. It assumes that you have some basic knowledge of what enzymes are and what they do. If you need more background information, your Biochemistry textbook or the Wikipedia article on enzymes are good places to start.

Recall that the surface of the influenza virion is covered with spikes of hemagglutinin and neuraminidase. Hemagglutinin is a protein that binds tightly to the sugar portions of various cell-surface glycoproteins by recognizing and binding the sugarsialic acid, which is also called N-acetyl neuraminic acid. Sialic acid is found at the terminus of the carbohydrate portions of many cell-surface glycoproteins and plays a key role in cell-cell and cell-virus binding. The human ABO blood-group antigens are examples of sialylated oligosaccharides that play an important role in medical biochemistry. Hemagglutinin permits the influenza virus to attach to a host cell during the initial infection, which in turn causes the viral RNA to enter the cell by endocytosis. This is a common mechanism for infection and we know that many viruses including HIV as well as parasites such as the Plasmodium that causes malaria attack host cells via their cell-surface carbohydrates. However, the tight grip of viral hemagglutinin on cell-surface sialic acid is a problem when new viral particles need to break away from the host cell.

The neuraminidase on the surface of the virion is necessary for new viral particles to break away from the host cell. Neuraminidase is a glycosidase (an enzyme that catalyzes the hydrolysis of glycosidic linkages) that specifically promotes the cleavage of sialic acid from glycoprotein saccharide chains. When the glycosidic linkage is cleaved by hydrolysis, the sialic acid falls off the cell surface. The viral particle is now no longer tethered to the host cell and can move off to infect other cells.

If the activity of neuraminidase is blocked, the new virions remain bound to the host cell and viral reproduction is prevented. You can view a Flash animation showing this concept here.

The structure of the influenza A neuraminidase N9 bound to an analogue of sialic acid has been determined by X-ray crystallography, and a simplified ribbon diagram is shown here. The amino acid chains are represented by the yellow ribbons, and the bound inhibitor as well as some key side chain groups are shown in ball-and-stick format. The broad arrows designate regions in which the amino acid chains form a "beta sheet" structure, with the arrow heads indicating the C-terminal end of the sheet. Cylindrical sections represent "random coil" regions of the amino acid sequence. Notice that there is essentially no helical structure in this enzyme. This image shows only one sub-unit of the biologically active form of the enzyme which is actually a tetramer of identical sub-units. The binding site of the enzyme does not vary from strain to strain. It consists of 18 amino acid residues of which 12 are in direct contact with the bound sialic acid analogue (and presumably with sialic acid in catalytically active situations). Four of these 12 are positively-charged arginines, while another 4 are negatively-charged glutamic and aspartic acid residues. The remainder are neutral (tyrosine, asparagine, isoleucine and tryptophan). If you visit the RCSB Protein Data Bank you can find X-ray structures of many neuraminidases - this one is indexed under the code "1nna". The details of the structure are discussed in the original paper by Bossart-Whitaker et al. cited below.

Mark von Itzstein and coworkers (then at the Monash University Victorian College of Pharmacy in Melbourne Australia and now at the Institute for Glycomics at Australia's Griffith University) studied the mechanism of sialic acid hydrolysis catalyzed by influenza A N9 neuraminidase. This enzyme is what is called a retaining glycosidase because if the starting glycoside has the α-configuration (as shown) then the product that is formed will also have the α-configuration. In common with many glycosidase enzymes, its active site features a pair of carboxyl residues (Asp 151 and Glu 277 in the N9 neuraminidase they studied) which play central roles in the enzyme's catalytic mechanism. The proposed mechanism is shown below.

There are two important transition states shown in this mechanism, the first for the actual cleavage of the C-O bond leading to loss of the ROH fragment and the second for the formation of a new C-OH bond. In the first transition state, notice how the enzyme assists the ionization of a water molecule, the transfer of its proton to the leaving OR group, and stabilizes the transient positive charge on the ring oxygen.

With knowledge of how the enzyme functioned, von Itzstein decided that a compound that looked like the carbohydrate in that key first transition state would be a good candidate for an anti-influenza drug that would function by preventing the release of viral particles from infected cells. Click here to go to the next stage in the story - synthesizing and testing a new compound.

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Wikipedia article about neuraminidase.

The story of how neuraminidase was identified as a target for anti-influenza drug development is briefly outlined by Graeme Laver, one of the key researchers in this field. You can read his March 2007 article in Education in Chemistry here.

Bossart-Whitaker, P.; Carson, M.; Babu, Y.S.; Smith, C.D.; Laver, W.G.; Air, G.M. J. Mol. Biol. 1993, 232, 1069–1083. (Link requires valid U of Manitoba Library ID).

von Itzstein, M. et al. Nature 1993, 363, 418-423. (Link requires valid U of Manitoba Library ID).

Treating the flu? Part 4: Developing Neuraminidase Inhibitors

Zanamivir (Relenza)

Note: this document should not be taken as any form of endorsement of the substances mentioned or as a recommendation for treatment.

With the information gained from structural and mechanistic studies on influenza A neuraminidase, von Itzstein and his team set out to devise and synthesize a stable molecule that looked sufficiently like the transition state to bind very tightly to the enzyme, thus inhibiting it. Recall that a transition state is not a stable isolable molecule, but it is possible to mimic the geometry of a proposed transition state with other chemical structures. These are called transition state analogues.

The proposed transition state for glycosidic bond cleavage in the mechanism previously outlined is shown here. Recall that for clarity the sugar structure has been simplified. It is evident that the reactive centre of the sugar ring is planar in this transition state. It is not possible to make a stable structure that has a double bond between position 2 and the ring oxygen similar to the partial double bond in the transition structure. Thus, von Itzstein et al. decided that a good inhibitor needed a double bond between positions 2 and 3 - that is, it should be a 2,3-dehydro derivative of sialic acid.

They also concluded that a strongly basic guanidino group should replace the hydroxyl at C-4 in the sialic acid structure. This would be positively charged at physiological pH and would bind strongly to a region of negative charge in the active site.

They synthesized and tested the structure shown in 1989 and found that it was indeed a potent and very selective inhibitor of influenza neuraminidase. Their synthetic route, published in the journal Carbohydrate Research in 1994, is shown below.

Although some of the reagents used in this synthesis may be unfamiliar, organic chemistry students should be able to recognize what is going on in each step. In the first step shown, the Lewis acid boron trifluoride etherate promotes an internal S_N2 reaction in which the carbonyl of the acetamide displaces the acetate ester to form the new ring. Notice the inversion of configuration at C4. This is then subjected to another S_N2 reaction in which the nucleophile is the azide anion N₃^-. The reagent is trimethylsilyl azide, which also provides mildly Lewis acidic activation for the displacement. Azide groups are excellent precursors for amines, and the reduction of the azide is easily carried out. You can see that some care must be taken here, since if the reaction is left too long the hydrogenation of the alkene will also occur. Simple alkaline hydrolysis removes the methyl ester and the acetate ester protecting groups, and then the amino group is converted into the desired guanidino function using formamidine sulfonic acid. This provided the desired neuraminidase inhibitor 4-deoxy-4-guanidino-2,3-dehydro-N-acetyl neuraminic acid, which ultimately has become the anti-influenza drug zanamivir (sold under the trade name Relenza by GlaxoSmithKline).

You can see how well zanamivir fits into the active site of influenza A neuraminidase from the X-ray crystal structure obtained by Zu et al. and indexed in theProtein Data Bank as 3b7e. This is an interesting structure because the enzyme is the neuraminidase from the A/Brevig Mission/1/1918 H1N1 strain, one of the viruses that caused the 1918 Spanish Flu. The genome of this virus was obtained from the frozen body of a woman who died in the Alaskan village of Brevig Missionin 1918. An interesting New York Times article describes the discovery of this virus (and incidentally the Johan Hultin who found the virus is no relation to Dr. Hultin!). It is another variation of the H1N1 strain that is at the centre of the 2009/2010 concern about Swine Flu.

The ribbon diagram has simplified the enzyme structure considerably - only those amino acids near the active site are shown, and only the most important ones that interact with zanamivir have their sidechains drawn. The drug molecule is shown in a space-filling representation in which oxygen is red, nitrogen is blue and carbon is white. Hydrogens are not shown. The diagram places the carboxylate group of zanamivir at the 6 o'clock position, while the guanidinium group is projecting backwards deep into the binding site. The hydroxylated sidechain is projecting forward at about 9 o'clock. The schematic drawing (based on a diagram from the book by Levy and Fugedi referenced below) shows the key contacts between the enzyme and the drug.

Numerous other synthetic routes to zanamivir have been published since the original synthesis shown here, and you can be very sure that the industrial synthesis isquite different. The problem with Zanamivir is that it cannot be administered orally. Because the guanidino group is strongly basic, if it were taken orally it would be protonated in the stomach. The resulting positively-charged structure could not be taken up from the gut. Zanamivir is usually administered by inhalation, but this is not as acceptable to many people as a pill would be, and does not give a particularly high level of bioavailability.

Given this problem with zanamivir, it is not surprising that others tried to find similar compounds to inhibit influenza neuraminidase that could be orally administered. Click here to find out about the second-generation drug oseltamivir (Tamiflu).

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von Itzstein, M.; Wu, W.-Y.; Jin, B. Carbohydrate Research 1994, 259, 301-305.

Taylor, N.R.; von Itzstein, M. J. Med. Chem. 1994, 37, 616–624.

Magano, J. Chem. Rev. 2009, in press. (You must have a valid U of Manitoba library ID to access the full-text article)

Xu, X.; Zhu, X.; Dwek, R.A.; Stevens, J.; Wilson, I.A. J.Virol. 2008, 82, 10493-10501.

Levy, D.; Fugedi, P. (Eds.) The Organic Chemistry of Sugars, CRC/Taylor & Francis: 2006.

Treating the flu? Part 4: Developing Neuraminidase Inhibitors

Other neuraminidase inhibitors

Research and development of new anti-influenza drugs has not stopped. The need for more effective drugs remains a powerful incentive for academic and industrial scientists, and there is of course a strong profit motive as well.

One compound that is now in clinical trials is peramivir, under development by BioCryst Pharmaceuticals. If you look at the structure of peramivir, you can see its family resemblance to other neuraminidase inhibitors. However, peramivir must be administered by injection because it has rather poor oral bioavailability. In fact, peramivir was initially developed by Johnson and Johnson but was abandoned because it was not orally active. Renewed interest in it as an injectable drug may be because only the most severe cases of influenza really need antiviral therapy, and such patients are likely already hospitallized.

Another new compound is CS-8958, from Japan's Daiichi Sankyo Co. Ltd. This compound is structurally very similar to zanamivir, differing only in the functionalization of the hydroxylated sidechain.

CS-8958 is a prodrug and not the active form. The octyl ester group is hydrolyzed in the liver, releasing the active neuraminidase inhibitor which only differs from zanamivir in having a methyl ether at the C7 position rather than a hydroxyl group. The main advantage of CS-8958 is that it is long-acting. Oseltamivir and zanamivir must be taken twice daily, but in a clinical study a single inhaled treatment with CS-8958 gave the same anti-influenza effect as twice-daily doses of oseltamivir over 5 days.

Palatin’s Bremelanotide Under Clinical Trials, Female Libido Enhancer

Female Libido Enhancer  – Bremelanotide

Bremelanotide is a compound that is currently under investigation for its potential uses in managing reperfusion injury, female sexual dysfunction or hemorrhagic shock. The chemical may also see success in managing modulate inflammation or limiting the effects of ischemia.

N-Acetyl-L-norleucyl-L-alpha-aspartyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-lysine (2-7)-lactam

Bremelanotide,  PT 141, CAS NO.: 189691-06-3

Synonym…..N-Acetyl-L-norleucyl-L-alpha-aspartyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-lysine (2-7)-lactam, Bremelanotide PT 141

Molecular FormulaC50H68N14O10

Molecular Weight1025.16

Palatin Technologies, Inc. INNOVATOR

Gedeon Richter….licensee

In May 2014, the company planned to file an NDA in the first half of 2016, and at that time, approval was expected in the first half of 2017

Bremelanotide i/ˌbrɛmɨˈlænətaɪd/ (formerly PT-141) is a compound underdrug development by Palatin Technologies as a treatment for female sexual dysfunction, hemorrhagic shock and reperfusion injury. It functions by activating the melanocortin receptors MC1R and MC4R, to modulate inflammation and limiting ischemia.[2] It was originally tested for intranasal administration in treating female sexual dysfunction but this application was temporarily discontinued in 2008 after concerns were raised over adverse side effects of increased blood pressure. As of December 2014, Palatin is conducting a human Phase 3 study[3] using a subcutaneous drug delivery system that appears to have little effect on blood pressure.

Palatin, in collaboration with European licensee Gedeon Richter, is developing an sc formulation of the synthetic peptide bremelanotide (PT-141; BMT), a melanocortin MCR-4 agonist and a synthetically modified analog of PT-14, also analogous to alpha-melanocyte-stimulating hormone (alpha-MSH), for the potential treatment of female sexual dysfunction (FSD) including hypoactive sexual desire disorder (HSDD)

The Bremelanotide or PT-141 is a mean that explains the revolution caused by the medical world in a silent but attractive manner in the human health related study. Bremelanotide is the latest arrival from the company called Palatin Technologies which forms the basic treatment for the hemorrhagic shock and reperfusion injury.( In short about the company, the Palatin Technologies is the owner of this research and is located in New Jersey. Hence this medicine is a Jersey based Product. And regarding the product under research, is waiting for the approval from the Food and Drug Association. Once this is done, the company has targeted to reach those customers, whom the Viagra has approached. This has the effect of helping the male patients suffering with an erectile dysfunction syndrome. Also if it gets the approval as a treatment measure for the female sexual dysfunction, then this medicine is expected to bring a relief to the post-menopausal and also supports or provides their sexual happiness and also they are checking regarding thehyposexual desire disorder. This is expected to be a blockbuster, if released. So this medicine is waiting for a confirmation as well as an approval.

In February 2015, a randomized, double-blind, placebo-controlled, open-label extension, phase III trial (NCT02338960; BMT-302, Reconnect Study) was initiated in the US in premenopausal women (expected n = 550) with hypoactive sexual desire disorder to evaluate the efficacy and safety of bremelanotide. At that time, the trial was expected to complete in July 2017

Study – Potential Use Erectile Dysfunction

One study has explored the potential use of bremelanotide as a replacement for natural peptide melanocyte stimulating hormones for the sake of treating erectile dysfunction.

• The goal of this study was to determine if the effects of bremelanotide stimulating sexual desire that was shown in male rats could be replicated in the brains of female rats. To do this, hormone primed female rats in a control group and a test group that were treated with bremelanotide and known to have consummatory sexual disorders was introduced to a group of male rats and the reactions were measured.

• Heart racing, hops and darts, pacing and customary sexual behaviors were assessed while the brain was stimulated. The stimulation of specific molecular markers within the brain was examined to determine arousal in the female subjects.

• Results indicated that the females saw an increase in sexual behavior when bremelanotide was applied to the limbic and hypothalamic regions of their brains. It is suggested that this was because the chemical that stimulated the mPOA terminals, leading to activated dopamine in the brain.

Additional study is necessary to determine the extent of the effects bremelanotide has on the brain and natural stimulating chemicals.

Bremelanotide and Ongoing Research

This is an advanced research involved even now. This functions by activating the Melanocortin, which is a group of peptide hormones which includes the adrenocorticotropic hormone and also the different forms of the melanocyte stimulating hormones. These melanocortins are produced or prepared from the proopiomelanocortin in the pituitary glands. The melanocortin releases or exert their effects by making a bind with the melanocortin and thereby activating it).The Bremelanotide functions by activating the melanocortin receptors and thereby makes a modulation in the inflammation. This is actually produced for making use in treating the sexual dysfunction. Due to certain reasons; the process of researching was kept under hold in recently, since it created some adverse side effects of increased blood pressure. In the chemistry of the preparation of the bremelanotide, the Peptide Melanaton II forms the basic compound. This compound is tested using a sunless tanning agent.

The actual information about the peptide melanaton has the effect of making sexual arousal and speed as well as sudden erections and some other side effects. However, there are several other measures taken to test the property of the same under several other health situations to make a detailed study about the chemical compound structure to make a change in the combination of the chemical structure. This medicine has made a revolution in the field of science of the human structure. When made a deep verification of the compound structure of the chemical study showed the following information. The structural design has an appearance of white colored powder like material, which has an accurate purity of nearly 98%. The actual molecular weight of the compound formed is around 1025.2. This compound has the collective share of Amino acids in the composition, peptide and acetate contents also.

The study of the compound structure PT-141 has an enhanced support of making a recombination that produces a different profile of the same medicine but in a different standard with different properties that may support the human requirement.

Bremelanotide PT-141 is known for its aphrodisiac properties

Development

Bremelanotide was developed from the peptide hormone Melanotan II which underwent testing as a sunless tanningagent. In initial testing, Melanotan II did induce tanning but additionally caused sexual arousal and spontaneous erections as unexpected side effects in nine out of the ten original male volunteer test subjects.[4]

In studies, bremelanotide was shown to induce lordosis in an animal model[5]and was also effective in treating sexual dysfunction in both men (erectile dysfunction or impotence) and women (sexual arousal disorder). Unlike Viagraand other related medications, it does not act upon the vascular system, but directly increases sexual desire via the nervous system.[6]

A Phase III clinical trial was scheduled to begin in the first half of 2007, but was delayed until August 2007. On August 30, Palatin announced that the U.S. Food and Drug Administration had expressed serious concerns regarding therisk/benefit ratio of bremelanotide with regards to the side effect of increased blood pressure. The FDA stated that it would consider alternate uses for bremelanotide, including as a treatment for individuals who do not respond to more established ED treatments. However, On May 13, 2008, Palatin Technologies announced it had “discontinued development of Bremelanotide for the treatment of male and female sexual dysfunction” while concurrently announcing plans to develop it as a treatment for hemorrhagic shock instead.[7] The company additionally announced intentions to focus its attention on another compound, PL-6983, that causes lower blood pressure inanimal models.[8]Palatin has since re-initiated Bremelanotide studies for ED and FSD using a subcutaneous delivery method. On August 12, 2009, the company announced that in a double-blind study of 54 volunteers bremelanotide failed to evoke the hypertensive side effects seen with the nasal delivery system used in prior studies, concluding that “variability of uptake” inherent in intranasal administration of the drug resulted in “increases in blood pressure and gastrointestinal events…primarily related to high plasma levels in [only] a subset of patients” and that subcutaneous administration of the drug circumvented the potential for this side effect.[8] Palatin has completed a human Phase 2B study utilizing subcutaneous administration and reported positive results.[9]

Structure

Bremelanotide is a cyclic hepta-peptide lactam analog of alpha-melanocyte-stimulating hormone (alpha-MSH) that activates the melanocortin receptorsMC3-R and MC4-R in thecentral nervous system. It has the amino acid sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH or cyclo-[Nle4, Asp5, D-Phe7, Lys10]alpha-MSH-(4-10). It is a metabolite of Melanotan II that lacks theC-terminal amide function.

BREMELANOTIDE

SYSTEMATIC (IUPAC) NAME
(3S,6S,9R,12S,15S,23S)-15-[(N-acetyl-L-norleucyl)amino]-9-benzyl-6-{3-[(diaminomethylidene)amino]propyl}-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaa zacyclotricosane-23-carboxylic acid
CLINICAL DATA
LEGAL STATUS	US: Unscheduled
PHARMACOKINETIC DATA
HALF-LIFE	120 minutes[1]
IDENTIFIERS
CAS NUMBER	189691-06-3
ATC CODE	None
PUBCHEM	CID 9941379
CHEMSPIDER	8116997
UNII	6Y24O4F92S
KEGG	D06569
CHEMBL	CHEMBL2070241
CHEMICAL DATA
FORMULA	C50H68N14O10
MOLECULAR MASS	1025.2 g/mol

Sexual dysfunction, including both penile erectile dysfunction or impotence and female sexual dysfunction, are common medical problems. Significant effort has been devoted over the last twenty or more years to develop methods, devices and compounds for treatment of sexual dysfunction. While more effort has been undertaken for treatment of penile erectile dysfunction, female sexual dysfunction is also an area to which significant research and effort has been devoted.

At present, one commonly used orally administered drug for treatment of sexual dysfunction in the male is Viagra®, a brand of sildenafil, which is a phosphodiesterase 5 inhibitor, increasing the persistence of cyclic guanosine monophosphate and thereby enhancing erectile response. There are several other medical treatment alternatives currently available depending on the nature and cause of the impotence problem. Some men have abnormally low levels of the male hormone testosterone, and treatment with testosterone injections or pills may be beneficial. However, comparatively few impotent men have low testosterone levels. For many forms of erectile dysfunction, treatment may be undertaken with drugs injected directly into the penis, including drugs such as papaverin, prostaglandin E1, phenoxybenzamine or phentolamine. These all work primarily by dilating the arterial blood vessels and decreasing the venous drainage. Urethral inserts, such as with suppositories containing prostaglandin, may also be employed. In addition, a variety of mechanical aids are employed, including constriction devices and penile implants.

A variety of treatments have also been explored for female sexual dysfunction, including use of sildenafil, although the Food and Drug Administration has not specifically approved such use. Testosterone propionate has also been employed to increase or augment female libido.

Melanocortin receptor-specific compounds have been explored for use of treatment of sexual dysfunction. In one report, a cyclic α-melanocyte-stimulating hormone (“α-MSH”) analog, called Melanotan-II, was evaluated for erectogenic properties for treatment of men with psychogenic erectile dysfunction. Wessells H. et al., J Urology 160:389-393 (1998); see also U.S. Pat. No. 5,576,290, issued Nov. 19, 1996 to M. E. Hadley, entitledCompositions and Methods for the Diagnosis and Treatment of Psychogenic Erectile Dysfunction and U.S. Pat. No. 6,051,555, issued Apr. 18, 2000, also to M. E. Hadley, entitled Stimulating Sexual Response in Females. The peptides used in U.S. Pat. Nos. 5,576,290 and 6,051,555 are also described in U.S. Pat. No. 5,674,839, issued Oct. 7, 1997, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Cyclic Analogs of Alpha–MSH Fragments, and in U.S. Pat. No. 5,714,576, issued Feb. 3, 1998, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Linear Analogs of Alpha–MSH Fragments. Melanotan-II is a peptide of the following formula:

Additional related peptides are disclosed in U.S. Pat. Nos. 5,576,290, 5,674,839, 5,714,576 and 6,051,555. These peptides are described as being useful for both the diagnosis and treatment of psychogenic sexual dysfunction in males and females. These peptides are related to the structure of melanocortins.

In use of Melanotan-II, significant erectile responses were observed, with 8 of 10 treated men developing clinically apparent erections, and with a mean duration of tip rigidity greater than 80% for 38 minutes with Melanotan-II compared to 3.0 minutes with a placebo (p=0.0045). The drug was administered by subcutaneous abdominal wall injection, at doses ranging from 0.025 to 0.157 mg/kg body weight. Transient side effects were observed, including nausea, stretching and yawning, and decreased appetite.

The minimum peptide fragment of native α-MSH needed for erectile response is the central tetrapeptide sequence, His6-Phe7-Arg8-Trp9 (SEQ ID NO:1). In general, all melanocortin peptides share the same active core sequence, His-Phe-Arg-Trp (SEQ ID NO:1), including melanotropin neuropeptides and adrenocorticotropin. Five distinct melanocortin receptor subtypes have been identified, called MC1-R through MC5-R, and of these MC3-R and MC4-R are believed to be expressed in the human brain. MC3-R has the highest expression in the arcuate nucleus of the hypothalamus, while MC4-R is more widely expressed in the thalamus, hypothalamus and hippocampus. A central nervous system mechanism for melanocortins in the induction of penile erection has been suggested by experiments demonstrating penile erection resulting from central intracerebroventricular administration of melanocortins in rats. While the mechanism of His-Phe-Arg-Trp (SEQ ID NO:1) induction of erectile response has not been fully elucidated, it has been hypothesized that it involves the central nervous system, and probably binding to MC3-R and/or MC4-R.

Other peptides and constructs have been proposed which are ligands that alter or regulate the activity of one or more melanocortin receptors. For example, International Patent Application No. PCT/US99/09216, entitled Isoquinoline Compound Melanocortin Receptor Ligands and Methods of Using Same, discloses two compounds that induce penile erections in rats. However, these compounds were administered by injection at doses of 1.8 mg/kg and 3.6 mg/kg, respectively, and at least one compound resulted in observable side effects, including yawning and stretching. Other melanocortin receptor-specific compounds with claimed application for treatment of sexual dysfunction are disclosed in International Patent Application No. PCT/US99/13252, entitledSpiropiperidine Derivatives as Melanocortin Receptor Agonists.

Both cyclic and linear α-MSH peptides have been studied; however, the peptides heretofore evaluated have had an amide or —NH2 group at the carboxyl terminus. See, for example, Wessells H. et al., J Urology, cited above; Haskell-Luevano C. et al., J Med Chem 40:2133-39 (1997); Schiöth H. B. et al.,Brit J Pharmacol 124:75-82 (1998); Schiöth H. B. et al., Eur J Pharmacol349:359-66 (1998); Hadley M. E. et al., Pigment Cell Res 9:213-34 (1996); Bednarek M. A. et al., Peptides20:401-09 (1999); U.S. Pat. Nos. 6,054,556, 6,051,555 and 5,576,290; and, International Patent Applications PCT/US99/04111 and PCT/US98/03298. While significant research has been conducted in an effort to determine the optimal structure of α-MSH peptides, including a variety of structure-function, agonist-antagonist, molecular modeling and pharmacophore studies, such studies have relied upon peptides with an art conventional —NH2 group at the carboxyl terminus. Further, it has long been believed that biologically active neuropeptides, including α-MSH peptides, are amidated, with an —NH2 group at the carboxyl terminus, and that such amidation is required both for biological activity and stability. See, for example, Metabolism of Brain Peptides, Ed. G. O’Cuinn, CRC Press, New York, 1995, pp. 1-9 and 99-101.

…………………………………………….

Bioorganic and Medicinal Chemistry Letters, 2005 ,  vol. 15,  4  pg. 1065 – 1068

http://www.sciencedirect.com/science/article/pii/S0960894X04014842

Figure 2.

NMR structural analysis on compound 3.

Figure 4.

NMR structural analysis of compound 1.

……………………………………………….

US6794489

In a preferred embodiment, the invention provides the peptide

Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH  Compound 1

The peptide of Compound 1 has a formula of C50H68N14O10, and a net molecular weight of 1025.18. This peptide may be synthesized by solid-phase means and purified to greater than 96% purity by HPLC, yielding a white powder that is a clear, colorless solution in water. The structure of Compound 1 is:

In general, the peptide compounds of this invention may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare the compounds of this invention.

The peptides of this invention may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. Where the compounds of this invention include an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.

The invention provides a pharmaceutical composition that includes a peptide of this invention and a pharmaceutically acceptable carrier. The carrier may be a liquid formulation, and is preferably a buffered, isotonic, aqueous solution. Pharmaceutically acceptable carriers also include excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as hereafter described.

EXAMPLE 1

Peptide Synthesis

The peptide Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH was synthesized by standard solid phase peptide synthesis methods, and is a cyclic heptapeptide melanocortin peptide analog with a free acid at the carboxyl terminus and an acetylated amino group at the amino terminus, with the structure:

The peptide has a net molecular weight of 1025.18, and is supplied in an acetate salt form. The peptide is a white, odorless amorphous hygroscopic powder, soluble in 0.9% saline, composed of C50H68N14O10. For synthesis, an Fmoc-Lys(R3)-p-alkoxybenzyl alcohol resin was transferred to a solid phase peptide synthesizer reactor with a mechanical stirrer. The R3group, such as 1-(1′-adamantyl)-1-methyl-ethoxycarbonyl (Adpoc), allyloxycarbonyl (Aloc) or 4-methyltrityl (Mtt), was removed and the next Fmoc-protected amino acid (Fmoc-Trp(Boc)-OH) was added to the resin through standard coupling procedures. The Fmoc protective group was removed and the remaining amino acids added individually in the correct sequence, by repeating coupling and deprotection procedures until the amino acid sequence was completed. After completion of coupling with the last Fmoc-amino acid derivative, Fmoc-Nle-OH, and cleavage of the Fmoc protective group, the exposed terminal amino group was acetylated with acetic anhydride and pyridine in N,N-dimethylformamide (DMF). The peptide-resin was dried and the Lys and Asp protective groups cleaved. The Lys and Asp deprotected peptide resin was suspended in a suitable solvent, such as DMF, dichloromethane (DCM) or 1-methyl-2-pyrrolidone (NMP), a suitable cyclic coupling reagent, such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) or N,N′-dicyclohexylcarbodiimide/1-hydroxybenzotriazole (DCCl/HOBt) was added, and coupling initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM). After cyclization, the peptide-resin was washed and the peptide cleaved from the resin and any remaining protective groups using trifluoroacetic acid (TFA) in the presence of water and 1,2-ethanedithiol (EDT). The final product was precipitated by adding cold ether and collected by filtration. Final purification was by reversed phase HPLC using a C18 column. The purified peptide was converted to acetate salt by passage through an ion-exchange column.

…………………………………………..

WO2014071339

Compounds of the Invention.

in a preferred embodiment of the present invention, fie rneianocortin receptor agonist is;

Ac-Nie”Cyc/o{-Asp-His–D–Phe-Arg–Trp»Lys)–OH (bremeianotide)

The peptide of bremeianotide has a formula of CsaHesN< C½, and a net mofecufar weight of 1025.18, This peptide may be synthesized by conventional means, including either solid-phase or Squid-phase techniques, and purified to greater than 99% purity by HPLC, yielding a white powder that is a clear, colorless solution in water. The structure of bremeianotide is:

in one embodiment of the invention, bremeianotide is synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of ‘well-known procedures utilizing a variety of resins and reagents may be used to prepare bremeianotide.

Bremeianotide may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacefie, maieic, citric, tartaric, oxalic, succinic or methanesu!fonic acid. The acetate salt form is especially useful.

in a preferred embodiment, bremelanotide is an acetate salt form, and is formulated in a buffered aqueous solution including giycerin, and prepackaged in a syringe and auto-injector device. In alternative embodiments, bremelanotide is any pharmaceutically acceptable salt form, and is formulated in any pharmaceutically acceptable aqueous solution, the aqueous solution optionally including one or more salts, such as sodium chloride, one or more acids, such as citric acid, and one or more additional ingredients, including cellulose or derivatives thereof, saccharides o

polysaccharides such as dextrose, and any of a wide variety of surfactants, chelating agents and preservatives.

………………………………………….

US20050222014

In yet another embodiment of the present invention, the melanocortin receptor agonist is:
Ac–Nle-cyclo(-Asp–His–D–Phe–Arg–Trp–Lys)-OH PT-141

The peptide of PT-141 has a formula of C50H68N14O10, and a net molecular weight of 1025.18. This peptide may be synthesized by conventional means, including either solid-phase or liquid-phase techniques, and purified to greater than 99% purity by HPLC, yielding a white powder that is a clear, colorless solution in water. The structure of PT-141 is:

In one embodiment of the invention, PT-141 is synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare PT-141.

PT-141 may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, citric, tartaric, oxalic, succinic or methanesulfonic acid. The acetate salt form is especially useful. Where the compounds of this invention include an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.

In a preferred embodiment, PT-141 is an acetate salt form, and is formulated in a buffered aqueous solution including glycerin, prepackaged in a metered unit dose intranasal delivery device. In alternative embodiments, PT-141 is any pharmaceutically acceptable salt form, and is formulated in any pharmaceutically acceptable aqueous solution, the aqueous solution optionally including one or more salts, such as sodium chloride, one or more acids, such as citric acid, and one or more additional ingredients, including cellulose or derivatives thereof, saccharides or polysaccharides such as dextrose, and any of a wide variety of surfactants, chelating agents and preservatives. In one preferred embodiment, PT-141 is administered to patients in volumes of 100 μL, with the quantity of PT-141 delivered determined by the concentration thereof. As described hereafter, in one preferred embodiment a metered unit dose contains 7.5 mg of PT-141.

While certain embodiments of the present invention are described primarily in the context of PT-141, it is to be understood that other melanocortin receptor agonists may be employed. For example, the metallopeptide melanocortin receptor agonists disclosed in WO 02/064091, filed on Feb. 13, 2001, and U.S. Ser. No. 10/640,755, filed on Aug. 13, 2003, both entitled Melanocortin Metallopeptides for Treatment of Sexual Dysfunction; and WO 01/13112, filed on Jun. 14, 2000, entitled Melanocortin Metallopeptide Constructs, Combinatorial Libraries and Applications, may be employed. In addition, the peptidomimetic melanocortin receptor agonists disclosed in U.S. Ser. No. 10/776,419, filed on Feb. 10, 2004, entitled Peptidomimetics of Biologically Active Metallopeptides; the pyrrolidine melanocortin receptor agonists disclosed in U.S. Ser. No. 10/766,657, filed on Feb. 10, 2004, entitled Pyrrolidine Melanocortin-Specific Compounds; and the bicyclic melanocortin receptor agonists disclosed in PCT/US04/01505, filed on Jan. 20, 2004, entitled Bicyclic Melanocortin-Specific Compounds, may also be employed. Also particular preferred are the piperazine melanocortin agonists disclosed in PCT/US04/01462, filed on Jan. 20, 2004 and U.S. Ser. No. 10/762,079, filed on Jan. 20, 2004, both entitled piperazine Melanocortin-Specific Compounds; the melanocortin agonists disclosed in WO 03/006620, filed on Jul. 11, 2002, entitled Linear and Cyclic Melanocortin Receptor-Specific Peptides; WO 04/005324, filed on Jul. 9, 2003, entitled Peptide Compositions for Treatment of Sexual Dysfunction; PCT/US00/18217, filed on Jun. 29, 2000 and U.S. Ser. No. 10/040,547, filed on Jan. 4, 2002, entitled Compositions and Methods for Treatment of Sexual Dysfunction; and U.S. Ser. No. 10/638,071, filed on Aug. 8, 2003, entitled Cyclic Peptide Compositions and Methods for Treatment of Sexual Dysfunction. The entire disclosure of each of the foregoing are incorporated here by reference. It is to be understood that the foregoing listing of patent applications disclosing melanocortin receptor agonists is intended to only be exemplary, and that other melanocortin receptor agonists, whether heretofore known or hereafter developed, may similarly be used in the practice of this invention.

…………………….

NMR prediction

H-NMR spectral analysis

13 C NMR PREDICTION

References

1.  King SH, Mayorov AV, Balse-Srinivasan P, Hruby VJ, Vanderah TW, Wessells H (2007).“Melanocortin receptors, melanotropic peptides and penile erection”. Current Topics in Medicinal Chemistry 7 (11): 1098–1106. doi:10.2174/1568026610707011111.PMC 2694735.PMID 17584130.
2.  Bremelanotide for Organ Protection and Related Indications, Palatin Technologies fact sheet. Retrieved on 2009-01-18.
3.  “Palatin Announces Start of Bremelanotide Phase 3 Program For Female Sexual Dysfunction”. PR Newswire. Retrieved 2015-02-17.
4.  “Tanning drug may find new life as Viagra alternative”. CNN. 1999. Retrieved2007-09-16.
5. Pfaus JG, Shadiack A, Van Soest T, Tse M, Molinoff P (July 2004).“Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist”. Proc. Natl. Acad. Sci. U.S.A. 101 (27): 10201–4. doi:10.1073/pnas.0400491101. PMC 454387.PMID 15226502.
6. Vicki Mabrey (2006). “ABC News “The Business of Desire – Love Potion””. ABC News. Retrieved 2009-01-24.
7.  “Palatin Technologies announces new strategic objectives and reports third quarter 2008 financial results”. Palatin Technologies press release. 2008. Retrieved 2008-08-21.
8.  “Palatin Technologies Announces New Strategic Objectives”. Retrieved2008-05-13.
9.  http://www.palatin.com/news/news.asp?ud=306

External links

• Palatin Technologies The company that has developed bremelanotide.
• US 6,794,489 bremelanotide (PT-141) patent (Appl. No.:040547)
• US 6,579,968 bremelanotide (PT-141) patent (Appl. No.:066501)
• Bremelanotide Edguider Forum

PALATIN TECHNOLOGIES, INC.: ‘Bremelanotide in Premenopausal Women With Female Sexual Arousal Disorder and/or Hypoactive Sexual Desire Disorder‘ CLINICALTRIALS.GOV (NCT01382719, [Online] 20 March 2012, page 1 Retrieved from the Internet: <URL:http://clinicaltrials.gov/archive/NCT01382719/ 2012-03 20> [retrieved on 2014-02-10]
2	*	PALATIN TECHNOLOGIES, INC.: ‘Reports Positive Bremelanotide Study; Improved Safety Profile with Subcutaneous Administration‘ PR NEWSWIRE., [Online] 12 August 2009, Retrieved from the Internet: <URL:http://www.thefreelibrary.com/Palatin+Technolo9ies,+Inc.+Reports+Positive+Bremel anotide+Study%38…-a020561 3302> [retrieved on 2014-02-10]
3	*	SAFARINEJAD, MR.: ‘Evaluation of the Safety and Efficacy of Bremelanotide, a Melanocortin Receptor Agonist, in Female Subjects with Arousal Disorder: A Double-Blind Placebo-Controlled, Fixed Dose, Randomized Study”.‘ INTERNATIONAL SOCIETY FOR SEXUAL MEDICINE. vol. 5, 2008, pages 887 – 897

US8455617	Jun 7, 2010	Jun 4, 2013	Astrazeneca Ab	Melanocortin receptor-specific peptides
US8455618	Oct 26, 2011	Jun 4, 2013	Astrazeneca Ab	Melanocortin receptor-specific peptides
US8487073	Nov 23, 2010	Jul 16, 2013	Palatin Technologies, Inc.	Melanocortin receptor-specific peptides for treatment of sexual dysfunction
US8729224	Jun 5, 2013	May 20, 2014	Palatin Technologies, Inc.	Melanocortin receptor-specific peptides for treatment of female sexual dysfunction
EP2266567A1	May 26, 2009	Dec 29, 2010	Æterna Zentaris GmbH	Use of cetrorelix in combination with PDE V inhibitors for the treatment of sex hormone dependent disorders
EP2266568A1	May 26, 2009	Dec 29, 2010	Æterna Zentaris GmbH	Use of LHRH antagonists in combination with PDE V inhibitors for the treatment of sex hormone dependent disorders
WO2013067309A1	Nov 2, 2012	May 10, 2013	Xion Pharmaceutical Corporation	Methods and compositions for oral administration of melanocortin receptor agonist compounds
WO2014071339A2*	Nov 5, 2013	May 8, 2014	Palatin Technologies, Inc.	Uses of bremelanotide in therapy for female sexual dysfunction

WO2009151714A2*	Mar 24, 2009	Dec 17, 2009	Palatin Technologies, Inc.	Therapeutic for treatment of circulatory shock, ischemia, inflammatory disease and related conditions
US6794489 *	Jan 4, 2002	Sep 21, 2004	Palatin Technologies, Inc.	Peptide sequence ac-nle-cyclo(-asp-his-d-phe-arg-trp-lys)-oh derived from a melanocyte-stimulating hormone (? alpha -msh?) analog, called melanotan-ii
US20050222014 *	May 26, 2005	Oct 6, 2005	Palatin Technologies, Inc.	Administering phosphodiestarase inhibitors and melanocortin receptor antagonist: synergistic mixture
US20110065652 *	Nov 23, 2010	Mar 17, 2011	Palatin Technologies, Inc.	Melanocortin Receptor-Specific Peptides for Treatment of Sexual Dysfunction

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KHAJURAHO INDIA

Location of Khajuraho Group of Monuments in India.

Location in Madhya Pradesh

1. Khajuraho Group of Monuments – Wikipedia, the free …

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   The Khajuraho Group of Monuments are a group of Hindu and Jain temples in Madhya Pradesh, India. About 620 kilometres (385 mi) southeast of New Delhi, …

Hotel Chandela – A Taj Leisure Hotel

LATUR, MAHARASHTRA, INDIA

http://en.wikipedia.org/wiki/Latur

LATUR लातूर LATTALUR, RATNAPUR
City
Latur Location in Maharashtra, India
Coordinates: 18.40°N 76.56°ECoordinates: 18.40°N 76.56°E
COUNTRY	India
STATE	Maharashtra
REGION	Aurangabad Division
DISTRICT	Latur
SETTLED	Possibly 7th century AD
GOVERNMENT
• BODY	Latur Municipal Corporation
• MAYOR	Akhtar Shaikh
AREA[1]
• TOTAL	117.78 km2(45.48 sq mi)
AREA RANK	89
ELEVATION	515 m (1,690 ft)
POPULATION (2011)
• TOTAL	382,754
• RANK	89th
• DENSITY	3,200/km2(8,400/sq mi)
DEMONYM	Laturkar
LANGUAGES
• OFFICIAL	Marathi
TIME ZONE	IST (UTC+5:30)
PIN	413 512 413 531
TELEPHONE CODE	91-2382
VEHICLE REGISTRATION	MH-24
SEX RATIO	923.54 ♀/1000 ♂
LITERACY	89.67
DISTANCE FROM MUMBAI	497 kilometres (309 mi) E (land)
DISTANCE FROMHYDERABAD	337 kilometres (209 mi) NW (land)
DISTANCE FROMAURANGABAD, MAHARASHTRA	294 kilometres (183 mi) SE (land)
CLIMATE	BSh (Köppen)
PRECIPITATION	666 millimetres (26.2 in)
AVG. SUMMER TEMPERATURE	41 °C (106 °F)
AVG. WINTER TEMPERATURE	13 °C (55 °F)
http://www.citypopulation.de/world/Agglomerations.html

his Is The Famous ‘Ganj-Golai’ As The Central Place Of The Latur City. There Are 16 Roads Connecting To This Place And Seperate Markets i.e. Jewellers …

लातूर जिल्हयातील चित्र संग्रह

1. Colleges and Universities
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   Rajarshi Shahu College…

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LATUR AIRPORT

LATUR AIRPORT

2012 Navratri Mahotsav in Latur

SOS Children’s Village Latur

Latur, India: Carnival Resort

Ausa Near Latur

Chakur near Latur

Vilasrao Deshmukh’s ancestral home at Babhalgaon village in Latur. Machindra Amle

UDGIR: Udgir is one of the most important towns of Latur district. Udgir has a great historical significance. It has witnessed the war between the Marathas …

The city of Latur is located in India’s welathiest state, Maharashtra. Together with many of the surrounding villages, Latur was all but destroyed in the

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